1-Alkyl-2-(pyridylsulfinylmethyl)-5-nitro-imidazoles and 1-alkyl-2-(pyridylsulfonylmethyl)-5-nitro-imidazoles

ABSTRACT

New 1-alkyl-2-(pyridyl-sulfinylmethyl)-5-nitro-imidazoles and 1alkyl-2-(pyridyl-sulfonylmethyl)-5-nitro-imidazoles are described according to the formula I   in which R stands for a methyl, ethyl or hydroxyethyl group and Z stands for a -SO- or -SO2- group and the pyridine ring is linked to the sulfinyl or the sulfonyl group in 2, 3 or 4 position as well as a process for their manufacture. The novel compounds have a pronounced activity against protozoae, especially trichomonads and amebae.

'United States Patent [191 Winkelmann et al.

[451 Sept. 16, 1975 l-ALKYL-2-(PYRIDYLSULFINYLMETHYL)- S-NITRO-IMIDAZOLES AND l-ALKYL-2-( PYRIDYLSULFONYLME- THYL)-5-NITRO-IMIDAZOLES [75] Inventors: Erhardt Winkelmann, Kelkheim Wolfgang Raether, Dreieichenhain, both of Germany [73] Assignee: Hoechst Aktiengesellschaft,

Frankfurt am Main, Germany [22] Filed: June 6, 1974 [21] Appl No.: 476,990

Primary Examiner-Henry R. .liles Assistant ExaminerBemard I. Dentz Attorney, Agent, or Firm-Curtis, Morris & Safford ABSTRACT New l-alkyl-2-(pyridyll-sulfinylmethyl )-5-nitroimidazoles and 1-alkyl-2-(pyridyl-sulfonylmethyl)-5- nitro-imidazoles are described according to the formulaI l (1) 0 M N 2 in which R stands for a methyl, ethyl or hydroxyethyl group and Z stands for a SO or SO group and the pyridine ring is linked to the sulfinyl or the sulfonyl group in 2, 3 or 4 position as well as a process for their manufacture.

The novel compounds have a pronounced activity against protozoae, especially trichomonads and amebae.

19' Claims, No Drawings 1-ALKYL-2-(PYRIDYLSULFINYLMETHYL)-5- NITRO-IMIDAZOLES AND 1-ALKYL-2-(PYRIDYLSULFONYLMETHYL)-5- NITRO-IMIDAZOLES The present invention relates to l-alkyl-2- (pyridylsulfinylmethyl)-5-nitro-imidazoles and to 1- alkyl-2-(pyridylsulfonylmethyl)-5-nitro-imidazoles and a process for their manufacture.

l(2-hydroxyethyl)2-methyl-5-nitroimidazole (Metronidazol) is known to be used for the treatment of protozoa! diseases, such as trichomoniasis and amebiasis.

Object of this invention are l-alkyl-2- (pyridylsulfinylmethyl)-5-nitro-imidazoles and l-alkyl- Z-(pyridylsulfonylmethyl)-5-nitroimidazoles of the formula] in which R is defined as above.

The l-alkyl-2-( pyridylthiomethyl )--nitroimidazoles of the formula II can be obtained, for example, by reacting l-alkyl-2-halogenomethyl-5-nitroimiclazoles of the formula III iycn x 0 1v (III) in which R is defined as above and X stands for a halogen atom or an arylsulfonic acid ester grouping, especially phenyl sulfonic acid or tolylsulfonic acid, with mercaptopyridines of the formula IV in which Y stands for a hydrogen atom or an alkali metal or ammonium ion in an aprotic solvent, such as xylene or dimethyl acetamide at elevated temperature. The l-alkyl-2-chloromethyl-5-nitroimidazoles of the formula III can themselves be obtained by reacting lalkyl-Z-hydroxymethyl-S-nitroimidaz0les with thionyl chloride.

The oxidation reactions are advantageously carried out by using once or twice the molar amount of an oxidizing agent. When treating the sulfides with a mol equivalent of the oxidizing agent, sulfoxides are obtained, the treatment with two mol equivalents of oxi dizing agent yields sulfones. Suitable oxidizing agents are, for example, hydrogen peroxide or per acids, such as, for example, peracetic acid, pertri fluoroaeetic acid or metachloroperbenzoic acid as well as nitric acid-or chromic acid or the salts thereof, moreover, permanganates, hypoc'hlorites, perchlorates, periodates and nitrogen oxide.

The oxidation reactions are advantageously carried out in a solvent or a dispersion agent. In this case, especially suitable solvents are those which are not attacked by the oxidizing agent, such as, for example, acetic acid, trifluoroacetie acid. When perbenzoic acid is used, methylene chloride or chloroform can also be used as solvents.

The oxidation reactions which are to lead to the sulfinyl compounds, are generally carried out at a temperature ranging from 10 to 30C. The sulfonyl compounds are generally obtained at oxidation temperatures ranging from 50 to C. Optionally the sulfonyl compounds may also be manufactured by oxidizing the corresponding sulfinyl compounds with the oxidizing agents mentioned at elevated temperature.

Depending on the mode of operation and the final product desired, the reaction times are in the range of from a few minutes to several hours.

The products of the invention are isolated by diluting the reaction solution with water and simultaneously precipitating or evaporating the organic solvent under reduced pressure. Optionally, the products can be purifled by recrystallization from a suitable solvent or mixture of solvents.

The l-alkyl-2-( pyridylsulfinylmethyl)-5-nitroimidazoles and l-alkyl-2-(pyridylsulfonylmethyl)5- nitro-imidazoles of the formula I are suitable for the treatment of protozoa] diseases in mammals, for example, those diseases caused by infections with Trichomonas vaginalis and Entamoeba histolytica. The novel products of the invention may be administered by the oral or local route. For the oral administration, the products are generally made into tablets or capsules containing, per daily dosage unit, about 10 to 750 mg of the active ingredient, in admixture with a usual diluent and/or excip'ient. For a local application, jellies, creams, ointments or suppositories may be used.

In addition to a good compatibility, the compounds of the invention are distinguished by a safe activity against trichomonads and amebae in vivo, which activity is substantially superior to the known pharmaceutical composition Metronidazol, as can be seen from the following Tables.

The following Examples illustrate the invention.

EXAMPLE 1 (test for activity) Activity against Trichomonas foetus was generally 3 4 tested on home-bred albino mice (NMRl-strain) of The body Weight of each animal was generally in the both sexes. The body weight of each animal was from range of from 50 to 60 grams. t 12 g The substance to be tested was administered orally The Substance to be tested was administered Orally by means of an oesophagal sound, either in an aqueous y means of an ocsophagal Sound either in an aqucous 5 solution or, in the case of sparingly water-soluble comsolution or, in the case of sparingly water-soluble compounds, in a Tylose SuSpensiOn- The Overall dosage was pounds, in a Tylose suspension. The overall dosage was administered in 2 units, the first 2 hours prior to infection and the second 2 hours after infection. 4 mice were used for each substance to be tested and for each dosage.

Infection was brought about by intraperitoneal injection of 19 million infective agents per animal in a suspension in 0.5 ml of a culture medium, Merck l. The comparison preparation Metronidazol was administered by the same route and in the same dosage as the substance to be tested (see Table I).

As infection controls there were generally used 10 administered in four units, the first 2 hours prior to infection, the second 2 hours after infection, the third 1 day after infection and the fourth 2 days after infection. 4 hamsters were used for each substance to be tested. Infection was brought about by intrahepatic injection of 130,000 infective agents per animal as a suspension in 0.1 ml of TTY medium (E. hisl.-Crithidia culture). The standard Metronidazol was administered by the same route and in the same dosage as the substance to be tested (see Table 2).

As infection controls there were generally used 10 mice which, after infection, were not treated any more. hamsters which Werei after infection, not treated y Another 5 mice served as a ero ontrol that is to ay 20 more. Another 5 hamsters served as a zero control, that these animals were neither treated nor infected. is to y, these animals r neither treated r in- Six days after infection, all the test animals were e t d. killed and the peritoneal exudate was examined for Six days at the earliest and 8 days at the latest after trichomonads. Mice which had died before were subinfection, all the animals were killed. Subsequently, the jected to the same examination. state of the liver was judged according to the degree of Th te s n e w j ge on h n n r icteric necrosis developed. Hamsters which had died tion of infective agents to be found in the peritoneal exd i the i d f i f ti were subjected to the udate on the 6th day after infection. For this purpose, Same examination the concentration of infective agents established with The Observations on the State of the liver Obtained the tested composition was compared with that of the with the tested composition and with the standard were comparison preparation and of the infection control. compared with those of the infection Controls The The scheme, according to which the tested substance and the standard were judged with regard to the concentration of infectants established, was the following: ineffective:

Concentration of infective agents was not substantially reduced as compared to infection control. Judgement: 3; 4

effective:

a. faint: Concentration of infective agents was mod erately reduced compared with infection control.

- Judgement: 2

scheme, according to which the liver findings (with tested compostion and standard) were judged, was the following:

ineffective:

l cteric necrosis did not show any substantial difference from that of infection controls. Possible judgement: 3; 4 (in rare cases: 2), effective:

a. faint: lcteric necrosis was less developed than with the infection controls. Possible judgement: freb. unsatisfactory: Concentration of infective agents q y 2 Far? Casesi was substantially reduced compared with infection b. unsatisfactory: lcteric necrosis was substantially control. Judgement: 1 reduced as compared to infection controls. Possie. no infective agents found. Judgement: 0 l j g n 0 rare p min n ly l;

2 in rare cases TABLE 1 0. good: no icteric necrosis was discovered. Judge- Concentration of ment 0 infectant 3- Composition dosage in mg/kg Trichomonas- TABLE 2 mouse, per os foetus in 4 mice I 2 X 00 0000 composition dozige E illverbfinktimgs 7 X 50 0000 go en amstu'. ntamoe a ISIIO ytica i X 0000 5 per os (extraintcstinal) 2 X g 0000 in 4 golden hamsters ll 2 X l()() 0000 2 X 50 0000 l 2 X 25 1022 4 X 100 0000 2 X l2.5 4343 4 X 50 0000 infection 4x 25 0000 control 4444 0 l 4 X I00 0000 l product of the invention: 4X 50 010] l-methyl-2-(2pyridylsullonylmicthyl)-5-nitmimidazole 4X 25 2023 [I comparative composilionl Metronidazol infection controls 4434 2 (test for activity) l Product of the invention l-mclhyl-lt Z-p rid lsull'onylmethyl )-5-nitro-imida7ole Activity against Entamoeba lustolyuca was generally 11 =cnmpnrutivt: composition: Metronidazol tested on cross-bred golden hamsters of both sexes.

EXAMPLE 3 (preparation of active substance):

1. l Methyl-2-(2 pyridylsulfonylmethyl)-5- nitroimidazole 25.0 g (0.1 mol) of l-methyl-2-(Z-pyridyIthiomethyl)-5-nitro-imidazole were dissolved in 400 ml of acetic acid and 2050 ml (0.2 mol) of 35 hydrogen peroxide were added dropwise at room temperature while stirring. There is no exothermic reaction. Then, the solution was stirred on the steam bath for 2 hours while heating. The reaction solution was evaporated under reduced pressure and the residue was recrystaL lized from water/alcohol.

Thus, 24.0 g of l-methyl-2-(2-pyridylsulfonylmethyl)-5-nitro-imidazole (corresponding to 85 of the theory) were obtained in the form of yellowish crystals which melted at 187C.

In an analogous manner, there were obtained with good yields,

2. l-Methyl-2-( 3pyridylsulfonylmethyl )-5- nitroimidazole from l-methyl-2-(3 pyridylthiomethyl)-5-nitroimidazole.

3. 1-Methyl-2-( 4-pyridylsulfonylmethyl.)-5- nitroimidazole (mp. 191C) from 1methyl-2-(4- pyridylthiomethyl )-5 -nitroimidazole.

4. l-Ethyl-2-( 2-pyridylsulfonylmethyl )-5- nitroimidazole from l-ethyl-2-(2-pyridylthiomethyl)- S-nitroimidazole.

5. l-Ethyl 2-( 3 -pyridylsulfonylmethyl )-5- nitroimidazole from l-ethyl-2-( 3-pyridylthiomethyl S-nitroimidazole.

6. l-Ethyl-2-( 4-pyridylsulfonylmethyl )-5- nitroimidazole from l-ethyl-2-(4-pyridylthiomethyl)- S-nitromidazole.

7. 1 (2-hydroxyethyl)-2-(2-pyridylsulfonylmethyl)-5- nitroimidazole from l-(2-acetoxyethyl)-2(2 pyridylthiomethyl)-5-nitroimidazole after saponifi cation of the acetyl group.

8. l-(2-hydroXyethyl)-2-(3-pyridylsulfonylmethyl)-5- nitroimidazole from- 1-( 2-acetoxyethyl )-2-( 3- pyridylthiomcthyl)-5-nitro-imidazole after saponification of the acetyl group.

9. 1-( 2-hydroxyethyl 2-( 4-pyridylsulfonylmethyl )-5- nitroim idazole from 1-( 2-acetoxyethyl )-2-( 4- pyridylthiomethyl)-5-nitroimidazole after saponifi cation of the acetyl group.

10. l -Mcthyl-2-( 2pyridylsulfinylmethy1)-5- nitroimidazole 25.0 g (0.1 mol) of l-methyl-2-(2 pyridylthiomethyl)-5-nitroimidazole were dissolved in 200 ml of chloroform and 17.25 g (0.1 mol) of mchloroperbenzoic acid, dissolved in 50 ml of chloroform, were added dropwise at room temperature. The

l-Methyl-2-( 3-pyridylsulfinylmethyl )5 1methyl-2-( 3-pyridylthiomenitroimidazole (mip. 1639C) from. l-meth-yl-2-( 4- pyridylthiomethyl)-5-nitroiniidazole. l3. 1-Ethyl 2(2-pyridylsulfinylmethyl)5- nitroimidazole (m.p.- 82C) from l-ethyl-2-(2- pyrid ylthiomethyl )-'5' nitroimidazol'e.

14: l-Ethyl-2-( 3-pyridylsulfin=ylmethyl )-5- nitroimidazole from 1'-ethyl-'2'-( 3-pyridylthiomethyl S-nitrdimidazole. 1

l5. 1-Ethy1-2-(4-pyridylsulfinylmethyl )-5- nitroimidazole from l-ethyl 2-(4-pyridylthiomethyl 5nitroimidazole.

16. l-(2-hydroxyethyl)-2 (2-pyridylsulfinylmethyl)-5- nitroimidazole from 1 2-acetoxyethyl )-2-( 2- pyridylthiomethyl)-5-nitroimidazole after saponifi cation of the acetyl group.

17. l-( 2-hydroxyethyl )-2-( 3-pyridylsulfinylmethyl )-5- nitroimidazole from 1 2-acetoxyethyl)-2-( 3- pyridylthiomethyl)-5-nitroimidazole after saponification of the acetyl group.

18. l( 2-hydroxyethyl)-2-( 4-pyridylsulfinylmethyl )-5- nitroimidazole from l 2-hydroXyethyl)-2-( 4- pyridylthiomethyl)-5-nitroimidazole after saponification of the acetyl group.

The l-alkyl-2(pyridylthiomethyl)-5-nitroimidazoles used as starting substances are prepared as described on page 2.

We claim:

1. A compound of the formula in which R stands for a methyl, ethyl or hydroxyethyl group and Z stands for SO or SO and the pyridine ring is linked to the sulfinyl or the sulfonyl group in 2, 3 or 4 position.

2. A compound of claim 1, which is l- Methyl-2-(2- pyridylsulfonylmethyl)-5-nitroimidazole.

3. A compound of claim 1, which is 1Methyl-2-(3- pyridylsulfonylmethyl)-5-nitroimidazo1e.

4. A compound of claim 1, which is 1Methyl-2-(4- pyridylsulfonylmethyl )-5-nitroimidazole.

5. A compound of claim 1, which is l-Ethyl-2-(2- pyridylsulfonylmethyl)-5-nitroimidazo1e.

6. A compound of claim 1, which is l-Ethyl-2-(3- pyridylsulfonylmethyl )-5-nitroimidazo1e.

7. A compound of claim 1, which is l-Ethyl-2-(4- pyridylsulfonylmethyl )-5-nitroimidazole.

8. A compound of claim 1, which is l-(2- Hydroxyethyl )-2-( 2-pyridylsulfonylmethyl )-5- nitroimidazole.

9. A compound of claim 1, which is l-(2- Hydroxyethyl )-2-( 3-pyridylsulfonylmethyl )-5 nitroimidazole.

10. A compound of claim 1, which is l-(2- Hydroxyethyl )-2-( 4-pyridylsulfonylmethyl )-5- nitroimidazole.

11. A compound of claim 1, which is 1-Methyl-2-(2- pyridylsulfinylmethyl)-5-nitroi:midazole.

12. A compound of claim 1, which is l-Methyl-2-( 3- pyridylsulfinylmethyl )-5-nitroimidazole.

17. A compound of claim 1, which is l-(2- nitroimidazolc.

18. A compound of claim 1, which is Hydroxyethyl )-2-( 3-pyridylsulfinylmethyl )-5- nitromidazole.

19. A compound of claim 1, which is Hydroxycthy )-2-(4-pyridylsulfinylmethyl )-5 nitroimidazole. 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1, which is 1-Methyl-2-(2-pyridylsulfonylmethyl)-5-nitroimidazole.
 3. A compound of claim 1, which is 1-Methyl-2-(3-pyridylsulfonylmethyl)-5-nitroimidazole.
 4. A compound of claim 1, which is 1-Methyl-2-(4-pyridylsulfonylmethyl)-5-nitroimidazole.
 5. A compound of claim 1, which is 1-Ethyl-2-(2-pyridylsulfonylmethyl)-5-nitroimidazole.
 6. A compound of claim 1, which is 1-Ethyl-2-(3-pyridylsulfonylmethyl)-5-nitroimidazole.
 7. A compound of claim 1, which is 1-Ethyl-2-(4-pyridylsulfonylmethyl)-5-nitroimidazole.
 8. A compound of claim 1, which is 1-(2-Hydroxyethyl)-2-(2-pyridylsulfonylmethyl)-5-nitroimidazole.
 9. A compound of claim 1, which is 1-(2-Hydroxyethyl)-2-(3-pyridylsulfonylmethyl)-5-nitroimidazole.
 10. A compound of claim 1, which is 1-(2-Hydroxyethyl)-2-(4-pyridylsulfonylmethyl)-5-nitroimidazole.
 11. A compound of claim 1, which is 1-Methyl-2-(2-pyridylsulfinylmethyl)-5-nitroimidazole.
 12. A compound of claim 1, which is 1-Methyl-2-(3-pyridylsulfinylmethyl)-5-nitroimidazole.
 13. A compound of claim 1, which is 1-Methyl-2(4-pyridylsulfinylmethyl)-5-nitroimidazole.
 14. A compound of claim 1, which is 1-Ethyl-2-(2-pyridylsulfinylmethyl)-5-nitromidazole.
 15. A compound of claim 1, which is 1-Ethyl-2-(3-pyridylsulfinylmethyl)-5-nitroimidazole.
 16. A compound of claim 1, which is 1-Ethyl-2-(4-pyridylsulfinylmethyl)-5-nitroimidazole.
 17. A compound of claim 1, which is 1-(2-Hydroxyethyl)-2-(2-pyridylsulfinylmethyl)-5-nitroimidazole.
 18. A compound of claim 1, which is 1-(2-Hydroxyethyl)-2-(3-pyridylsulfinylmethyl)-5-nitromidazole.
 19. A compound of claim 1, which is 1-(2-Hydroxyethy)-2-(4-pyridylsulfinylmethyl)-5-nitroimidazole. 